Department of Obstetrics and Gynecology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan.
Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Sci Rep. 2022 Jul 27;12(1):11673. doi: 10.1038/s41598-022-15656-y.
Dysregulation of transcriptional programs that are tightly regulated by DNA methylation during placental and fetal development at different gestational stages, may cause recurrent miscarriage. Here, we examined genome-wide DNA methylation in chorionic villi and decidual tissues from patients suffering RM and from healthy women who had undergone artificial abortion (n = 5 each). We found that 13,426 and 5816 CpG sites were differentially methylated in chorionic villi and decidua, respectively. DNA methylation profiles of chorionic villi, but not decidua, in RM patients was clearly distinct from AA controls. Among the differentially methylated genes, the enhancer region of SPATS2L was significantly more highly methylated in RM patients (n = 19) than AA controls (n = 19; mean methylation level, 52.0%-vs.-28.9%, P < 0.001), resulting in reduced expression of SPATS2L protein in the former. Functionally, depletion of SPATS2L in extravillous trophoblast cells decreased their invasion and migration abilities. Our data indicate that particularly the chorionic villi in RM patients exhibit distinct DNA methylation profiles compared with normal pregnancies and that this changed DNA methylation status may impede the progression of embryo development via the altered expression of genes such as SPATS2L in the villi.
在不同的妊娠阶段，胎盘和胎儿发育过程中受 DNA 甲基化严格调控的转录程序失调，可能导致复发性流产。在这里，我们检查了来自患有 RM 患者的绒毛膜和蜕膜组织以及经历人工流产的健康女性（每组各 5 例）的全基因组 DNA 甲基化。我们发现，绒毛膜和蜕膜中的 13426 个和 5816 个 CpG 位点分别存在差异甲基化。RM 患者绒毛膜的 DNA 甲基化图谱明显不同于 AA 对照组，但蜕膜则不然。在差异甲基化基因中，RM 患者（n=19）的 SPATS2L 增强子区域的甲基化程度明显高于 AA 对照组（n=19；平均甲基化水平，52.0%-vs.-28.9%，P<0.001），导致前者 SPATS2L 蛋白表达减少。功能上，外滋养层细胞中 SPATS2L 的耗竭降低了它们的侵袭和迁移能力。我们的数据表明，与正常妊娠相比，RM 患者的绒毛膜尤其表现出独特的 DNA 甲基化图谱，这种改变的 DNA 甲基化状态可能通过改变 SPATS2L 等基因在绒毛中的表达来阻碍胚胎发育的进程。
